Clinical Conundrum Research Articles

Category II Intrapartum Fetal Heart Rate Patterns Unassociated With Recognized Sentinel Events: Castles in the Air.

The evolution of continuous electronic fetal heart rate (FHR) monitoring has presented the obstetrician with a critical clinical conundrum: basic science observations suggest that such monitoring might be associated with improved long-term neurologic outcomes, yet, after a half century of use and millions of cesarean deliveries based on FHR monitoring, evidence for such improvement remains absent. This dichotomy appears to be related to widespread misconceptions regarding the physiology underlying various FHR patterns and the developmental origins of cerebral palsy. These misconceptions are strengthened by a reliance on anecdotal experience and tradition in lieu of evidence-based medicine, the confusing "category II" FHR designation, medical-legal considerations, and our tendency to view fetal monitoring, as originally conceptualized, as a single, indivisible entity whose concepts must be accepted or rejected en bloc. Ill-defined and largely imaginary conditions such as "depletion of fetal reserve" are particularly harmful and their use in clinical medicine uniquely not evidence based. A solution to this self-inflicted injury to our specialty will require a concerted effort involving teachers, authors, and researchers.

Cases from a Community Hospital… JCHIMP Series #1: 55-Year-Old Male with Acute PE Who Developed Persistent Epistaxis.

This is the first in a new series of case reports that will present real scenarios from our community hospital. The cases are chosen to highlight clinical dilemmas and offer review and perspective on what is currently known about the topic.We present the case of a 55-year-old Caucasian male who presented to the emergency department of our community hospital for worsening dyspnea. Evaluation in the Emergency department revealed a diagnosis of extensive pulmonary emboli in the pulmonary vasculature. The patient was admitted to the ICU. A clinical decision was made to initiate treatment with low-dose tissue plasminogen activator (tpa) followed by intravenous heparin infusion. Several hours later the patient developed significant epistaxis. A decision was made to stop the heparin infusion. Later that day, the patient had abrupt clinical deterioration with subsequent cardiac arrest and did not recover. We discuss the classification and treatment of acute pulmonary embolism, the management of epistaxis in an anticoagulated patient, and the clinical conundrum of balancing active bleeding in patient requiring anticoagulation.

The Vascular Basis of Takotsubo Syndrome

Takotsubo Syndrome (TTS) is an unmet medical need as there is no “standard of care” with an in‐hospital mortality rate equivalent to patients with an acute myocardial infarction. Characteristic of TTS is systolic ballooning of the left ventricular (LV) apex, simultaneous with contraction of the base. The mechanism(s) underlying this disassociation of mechanical activities in the LV is(are) unknown, however, a murine model may provide insights into this clinical conundrum. Previously, we found that mice null for Kv1.5 channels (KO), a model of inadequate coronary metabolic dilation, exhibit TTS (KOTTC) when stressed by transaortic constriction (TAC). Because of the microvascular link to inadequate dilation, we hypothesized that coronary vessels in the base and the apex of the left ventricle have different phenotypes as shown by variations in gene expression. To address this, we dissected small coronary arteries from the LV apex and base of KO control mice (KOC) and following TAC when the mice exhibited profound TTS. Ventricular function (fractional shortening [FS]) was calculated from echocardiographic (Echo) imaging. The Echo measurements revealed FS of 39±3% and 34±6% in LV base and apex, respectively, in KOC (P=NS). In contrast, FS was significantly changed in KOTTC with FS of ‐9±4% in LV apex and 25±11% in the base (P<0.05, with the negative FS representing systolic ballooning). After the Echo measurements, hearts were removed, placed in a chilled dish, and vessels immediately isolated from the LV apex and base (using a dissecting microscope) were placed in Trizol and flash frozen. Total RNA was extracted and used for RNAseq to profile the transcriptomes of small arteries from the apex and base of KOC and KOTTC groups. RNAseq revealed expression of 197 genes significantly changed in the LV apex versus base of KOTTC mice (P<0.05). The 197 genes represented 24 distinct pathways with some of the most significant comprising neuroactive‐receptor ligand interactions, miRs in cancer, and complement and coagulation cascades. The endothelin pathway was significantly upregulated in small arteries of the LV apex compared to base in KOTTC. Moreover, 460 genes were differentially expressed between the apex of KOTTC versus KOC (P<0.05) representing 37 pathways, including miR’s in cancer and cytokine signaling. The changes in miR expression in cancer may also denote changes associated with cell differentiation and apoptosis. These changes support our concept that regional, apex vs base, differences in vascular gene expression may underlie the basis of Takotsubo Syndrome.

Clinical conundrum

Abstract Julia Tang considers the case of a Border Collie seen at Highcroft Veterinary Hospital, Bristol, following two episodes of haemorrhage from the oral cavity.

Abstract #1163589: Methimazole-induced Agranulocytosis

Agranulocytosis, a well-reported but rare, life-threatening side effect of methimazole, creates a clinical conundrum in the management of hyperthyroidism. We present a case of methimazole-induced agranulocytosis in a patient with Graves’ disease, subsequently treated with total thyroidectomy.

Memory reconsolidation and the crisis of mechanism in psychotherapy

Internal mechanisms of lasting therapeutic change have eluded empirical identification despite decades of outcome research. A breakthrough may be at hand in neurobiological research on memory reconsolidation (MR), which has identified (a) a fundamental mechanism of the brain capable of targeted, profound unlearning and nullification of subcortical emotional learnings and the behaviors and states of mind they generate, and (b) the specific experiences required by the brain for such unlearning. We review the empirically identified process of annulment of emotional learnings, show that it fulfills clinical theorists' criteria for a mechanism of change, and define an empirical study to validate or falsify this MR mechanism's hypothesized clinical occurrence and causal role in therapeutic change. Extensive preliminary clinical observations of transformational change, also described, strongly support the causal role of the mechanism. The MR framework could significantly advance psychotherapy effectiveness and unification, and resolve longstanding clinical conundrums and controversies.

Restarting anticoagulant therapy after intracranial hemorrhage in patients with atrial fibrillation: A nationwide retrospective cohort study.

Resuming anticoagulation after an intracranial hemorrhage (ICH) poses a clinical conundrum. The absence of relevant guidelines has led to wide variations in the decision on resuming anticoagulation therapies after ICH. This study aimed to evaluate the risks of an anticoagulation therapy on severe thrombotic events (STE) and severe hemorrhage events (SHE) in Korea and compare the effects of novel direct oral anticoagulants (NOACs) and warfarin in patients with AF. This study was performed using the Korean national health insurance claims data obtained between 2002 and 2017 from individuals who had recently survived an ICH with comorbid AF. The endpoints of this study were STE and SHE. Anticoagulants, antiplatelet agents, and non-antithrombotic users were analyzed for survival with propensity score matching. Among the 4,964 participants analyzed, 878 (17.7%) and 2,070 (41.7%) used anticoagulant and antiplatelet agents, respectively. Anticoagulant (hazard ratio [HR] for STE: 0.385, P<0.0001; HR for SHE: 0.578, P<0.0001) or antiplatelet users (HR for STE: 0.545, P<0.0001; HR for SHE: 0.637, P<0.0001) had a lower risk of STE and SHE than non-antithrombotic users. Anticoagulation 6-8weeks post-ICH showed a tendency of the lowest risk of all-cause mortality (HR: 0.614, P=0.0552). However, there was no difference in the risk between the anticoagulant and antiplatelet users. Further, NOACs were associated with a lower risk of STEs than warfarin (HR, 0.263; P<0.0001). Our results showed that in patients with AF, resuming anticoagulants and antiplatelets after ICH improved the STEs and SHEs. Further, NOAC had additional benefits as compared to warfarin.

Complex Persistent Opioid Dependence-an Opioid-induced Chronic Pain Syndrome.

Long-term opioid therapy (LTOT) for chronic cancer and non-cancer pain is commonly ineffective in providing its stated goal of improving function through good control of pain. Opioid tapering (slow dose reduction and/or discontinuation), the logical solution, also appears to be ineffective among many patients on LTOT as it often leads to even worse pain control and function, leaving the patients and providers managing LTOT in a clinical conundrum with little treatment choices. Complex persistent opioid dependence (CPOD) was recently offered as a heuristic to explain this clinical conundrum exemplified by the ineffectiveness of both LTOT and opioid tapering. This manuscript provides a detailed description of the neurobehavioral underpinnings of CPOD, explaining how long-term opioid use can lead to more pain even while experiencing relief with each opioid dose. CPOD is characterized by the allostatic opponent mechanisms of neuroadaptations related to the progression of opioid dependence and tolerance involving nociceptive/anti-nociceptive brain systems causing opioid-induced hyperalgesia and reward/anti-reward systems causing hyperkatefia or suffering that induces pain experience through the cognitive/emotional component of pain mechanisms. "Opioid Induced Chronic Pain syndrome" (OICP) is offered as an alternate clinical diagnostic term instead of CPOD that has several limitations as a diagnosis term including poor patient acceptance due to stigma towards addiction and clinical confounding with opioid use disorder, a related but separate clinical entity. OICP with LTOT is conceptualized as a recoverable iatrogenic problem that can be managed by pain providers. Broad guidance on management of OICP is also provided.

Clinical conundrum

Emily Stacey presents a case of non-resolving pneumonia in a middle-aged cat on immunosuppressive therapy for atopy, that she saw when working at Wanstead Veterinary Hospital, part ofthe Goddard Veterinary Group.

Hypertensive Disorders of Pregnancy: Common Clinical Conundrums.

Hypertensive complications of pregnancy comprise 16% of maternal deaths in developed countries and 7.4% of deaths in the United States. Rates of preeclampsia increased 25% from 1987 to 2004, and rates of severe preeclampsia have increased 6.7-fold between 1980 and 2003. The aim of this study was to review current and available evidence for common clinical questions regarding the management of hypertensive disorders of pregnancy. Original research articles, review articles, and guidelines on hypertension in pregnancy were reviewed. Severe gestational hypertension should be managed as preeclampsia with severe features. Serum uric acid levels can be useful in predicting development of superimposed preeclampsia for women with chronic hypertension. When presenting with preeclampsia with severe features before 34 weeks, expectant management should be considered only when both maternal and fetal conditions are stable. In the setting of hypertensive disorders of pregnancy, oral antihypertensive medications should be initiated when systolic blood pressure is greater than 160 mm Hg or when diastolic blood pressure is greater than 110 mm Hg, with the most ideal agents being labetalol or nifedipine. Furthermore, although risk of preeclampsia recurrence in future pregnancy is low, women with a history of preeclampsia should be managed with 81 mg aspirin daily for preeclampsia prevention. Despite the frequency with which hypertensive disorders of pregnancy are encountered clinically, situations arise frequently with limited evidence to guide providers in their management. An urgent need exists to better understand this disease to optimize outcomes for impacted patients.

Multisystem Inflammatory Syndrome in Children and Kawasaki Disease: A Clinical Conundrum

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in general leads to a mild disease in children, but a rare yet serious complication of multisystem inflammatory syndrome in children (MIS-C) has been reported.1 MIS-C cases are on the rise during the COVID-19 pandemic, and clinical features overlap between MIS-C and an already well-known clinical entity in children: Kawasaki disease (KD). Both KD and MIS-C are diagnoses of exclusion, and can present with acute fever and increased inflammatory markers without any other potential etiology.2 Despite the overlap in clinical presentation, there are some differentiating features that could help establish an accurate diagnosis and appropriate management, which are highlighted in this article.

Construction and Validation of Convenient Clinicopathologic Signatures for Predicting the Prognosis of Stage I-III Gastric Cancer.

BackgroundPatients with stage I-III gastric cancer (GC) undergoing R0 radical resection display extremely different prognoses. How to discriminate high-risk patients with poor survival conveniently is a clinical conundrum to be solved urgently.MethodsPatients with stage I-III GC from 2010 to 2016 were included in our study. The associations of clinicopathological features with disease-free survival (DFS) and overall survival (OS) were examined via Cox proportional hazard model. Nomograms were developed which systematically integrated prognosis-related features. Kaplan–Meier survival analysis was performed to compare DFS and OS among groups. The results were then externally validated by The Sixth Affiliated Hospital, Sun Yat-sen University.ResultsA total of 585 and 410 patients were included in the discovery cohort and the validation cohort, respectively. T stage, N stage, lymphatic/vascular/nerve infiltration, preoperative CEA, and CA19-9 were independent prognostic factors (P < 0.05). Two prognostic signatures with a concordance index (C-index) of 0.7502 for DFS and 0.7341 for OS were developed based on the nomograms. The 3-year and 5-year calibration curves showed a perfect correlation between predicted and observed outcomes. Patients were divided into three risk groups (low, intermediate, high), and distinct differences were noticed (p < 0.001). Similar results were achieved in the validation cohort. Notably, a free website was constructed based on our signatures to predict the recurrence risk and survival time of patients with stage I-III GC.ConclusionsThe signatures demonstrate the powerful ability to conveniently identify distinct subpopulations, which may provide significant suggestions for individual follow-up and adjuvant therapy.

Hemophagocytic Lymphohistiocytosis Associated With Endocarditis: A Case Years in the Making.

Hemophagocytic Lymphohistiocytosis Associated With Endocarditis: A Case Years in the Making.

Clinical conundrum

Abstract Carla Asorey Blazquez and Ferran Valls Sanchez describe a case of a 1-year-old French Bulldog with weight loss, chronic vomiting and diarrhoea, seen at Dick White Referrals.

Efficacy and Costs of Three Pharmacotherapies for Patent Ductus Arteriosus Closure in Premature Infants

The hemodynamic impact of persistent patent ductus arteriosus (PDA) is associated with neonatal morbidities and mortality in preterm newborns. While there has been considerable debate about optimal management of PDA and its impact on clinical outcomes, there is widespread variation in practice, such as using different pharmacotherapies to achieve closure of hemodynamically significant PDA during the first week of life in very low birth weight infants. The objective was to estimate the efficacy of acetaminophen, ibuprofen, and indomethacin with regard to ductal closure and to compare the costs of these three commonly used medications to treat PDA in preterm infants. PubMed, Embase, and Cochrane Registry were searched for trials from the years 2010-2020. We identified 17 randomized clinical trials (RCTs) and 14 case series that enrolled preterm infants <37 weeks gestational age for inclusion. Pooled estimates of closure rates for acetaminophen (n = 630), ibuprofen (n = 694), and indomethacin (n = 312) were analyzed using the weighted proportion ratio using a Mantel‑Haenszel random effects model. The chi-squared test of proportions was used to determine significance between groups. We accessed cost estimates of pharmacotherapy from the Lexi-Comp average wholesale price database and utilized a decision tree model to appraise cost benefits for the outcome measure of successful PDA closure. The pooled proportional point estimates of closure rates from RCTs for acetaminophen, ibuprofen, and indomethacin were 70.1% (95% confidence interval [CI] 60-80), 63.4% (95% CI 52.8-74.1), and 71.5% (95% CI 62.3-80.7), respectively. There was no significant statistical difference in closure rates when RCTs and uncontrolled case series were combined. Pairwise comparisons showed both acetaminophen and indomethacin were each more effective in closing PDA than ibuprofen (acetaminophen vs indomethacin: p = 0.01; ibuprofen vs indomethacin: p = 0.02; acetaminophen vs indomethacin: p = 0.93). Comparing costs for successful closure of PDA, at the average wholesale price of different medications, suggested that treatment with acetaminophen costs significantly less, with a mean of $1487 (95% CI 1300-1737), compared to ibuprofen, with a mean of $2585 (95% CI 2214-3104), and indomethacin, with a mean of $2661 (95% CI 2358-3052), per course of treatment. Our meta-analysis suggests acetaminophen is non-inferior to both indomethacin and ibuprofen, and costs relatively less for successful PDA constriction in premature infants. Further clinical trials are warranted to compare acetaminophen's safety, along with short- and long-term effects, to help resolve the clinical conundrum of the necessity of early treatment in the management of PDA, and the optimal pharmacological course, if indicated.

Tumor markers are associated with rapidly progressive interstitial lung disease in adult-dermatomyositis.

DM-associated rapidly progressive interstitial lung disease (DM-RP-ILD) has been the clinical conundrum. We assess the serum levels of tumor markers (TMs) in different types of ILD, and explore the diagnostic utility of TMs for DM/ADM-RP-ILD. This was a retrospective cohort study, data including clinical and laboratory records were collected from the first affiliated hospital of Zhengzhou University from December 2015, to June 2020. Tumor markers (TMs) include CEA, CA153, CA724, CA125, and CA199. Spearman analysis, ROC, and Kaplan-Meier curve were used for data analysis. Total 272 patients (149 DM and 123 ADM) were enrolled, 152 (55.88%) with ILD (116 with chronic ILD, 36 with RP-ILD) and 120 (44.12%) without ILD among them. The serum levels of CEA and ferritinwere significantly higher in patients with RP-ILD than in the other two groups. Serum CA125, CA199, and CA153 levels in patients with RP-ILD were higher than those without ILD. CEA levels were associated with the ferritin, KL-6 and anti-MDA5 levels, and CEA concentration was significantly negatively correlated with DLco (P = 0.016, R2 = - 0.281). CEA [AUC = 0.7, 95% CI = (0.594, 0.806)] and ferritin [AUC = 0.737, 95% CI = (0.614, 0.860)] had diagnosed value for patients developing RP-ILD. Patients with high serum CEA levels had higher mortality rate within the DM-ILD population. TMs and ferritin were increased in DM/ADM-RP-ILD, and serum CEA and CA153 levels can evaluate disease severity of DM. And CEA and ferritin can be used as noninvasive diagnostic biomarkers for patients with DM-RP-ILD. Key Points • Interstitial lung disease (ILD) is a serious complication of DM, and is a leading cause of mortality, especially rapidly progressive ILD. • Tumor markers as a kind of noninvasive detection can reflect the disease severity of DM, and CEA and ferritin can be used to identify patients with RP-ILD.

Clinical conundrum

Abstract Emma Holt of CVS Advanced Clinical Services Network presents a case of dysuria in a Bichon Frise she saw whilst working at Moorview Referrals.

Ligand-mediated PAI-1 inhibition in a mouse model of peritoneal carcinomatosis

SummaryPeritoneal carcinomatosis (PC) present a ubiquitous clinical conundrum in all intra-abdominal malignancies. Via functional and transcriptomic experiments of ascites-treated PC cells, we identify STAT3 as a key signaling pathway. Integrative analysis of publicly available databases and correlation with clinical cohorts (n = 7,359) reveal putative clinically significant activating ligands of STAT3 signaling. We further validate a 3-biomarker prognostic panel in ascites independent of clinical covariates in a prospective study (n = 149). Via single-cell sequencing experiments, we uncover that PAI-1, a key component of the prognostic biomarker panel, is largely secreted by fibroblasts and mesothelial cells. Molecular stratification of ascites using PAI-1 levels and STAT3 activation in ascites-treated cells highlight a therapeutic opportunity based on a phenomenon of paracrine addiction. These results are recapitulated in patient-derived ascites-dependent xenografts. Here, we demonstrate therapeutic proof of concept of direct ligand inhibition of a prognostic target within an enclosed biological space.

Conundrums of coronary brachytherapy

PurposeIn the 1998–2005 heyday of intravascular coronary brachytherapy, a variety of delivery devices were developed and marketed. As the industry shrank, only one device, the Novoste Beta-Cath 3.5F System (Best Vascular, Norcross, GA) remained in commercial production. The 2008 instruction manual, the only official source of technical guidance, lacks recommendations for various common scenarios. Methods and MaterialsThe clinical conundrums described here were encountered during regular use of the Novoste system in 81 patients treated from January to December of 2020 in the course of using the Novoste device in accordance with the 2008 manufacturer's instruction manual. Our experience and strategies are reported and critiqued. ResultsAmbiguous patient selection factors include vein grafts, multiple affected vessels, large vessels, retreatment, multiple overlapping stents and prior radiation. Procedural ambiguities include vessel size determination, proper prescription dose, very long lesions and eccentric source positioning. Potential procedural mishaps include stuck sources and the risk of contamination. ConclusionsThe Novoste intravascular coronary brachytherapy system is the only commercially available brachytherapy delivery catheter, and may remain so for some time. The issues detailed here provide insight and guidance for current users and may prompt research into areas lacking adequate information.

Is Patch Test Necessary in Children to Solve the Clinical Conundrum of Foot Eczema.

Foot eczema in children is a commonly encountered condition but is associated with diverse etiology, thereby posing a diagnostic challenge. These include atopic eczema, juvenile plantar dermatoses, irritant contact dermatitis, and allergic contact dermatitis. Because of the diverse etiology, it is often difficult to distinguish between the conditions clinically, thereby warranting patch testing for the correct diagnosis. The study was conducted to determine the frequency of positive patch tests among children with foot eczema and to compare them with children with and without atopy. This was a prospective observational study done on 86 children aged 4 to 17 years presenting with foot eczema in whom patch testing was done using Indian standard series and footwear series and patients' own footwear. The clinical diagnosis of foot eczema in our study was allergic contact dermatitis (37%), followed by atopic eczema (30%), juvenile plantar dermatoses (17%), and lichen simplex chronicus (15%). Patch test positivity was present in 36% of the cases with clinical relevance in 65% of the cases. The common allergens were rubber allergens and disperse dyes. Of the children who were patch tested, highest patch test positivity rates were seen in allergic contact dermatitis (50%) and juvenile plantar dermatoses (53%). No significant differences were observed with regard to patch test positivity or relevance between children with and without atopy. The diagnosis of foot eczema in children cannot be made on clinical grounds alone, and patch testing should be recommended in children with any morphological pattern of foot eczema irrespective of presence or absence of atopy, especially in those with long-standing and recalcitrant disease with frequent exacerbations.